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Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Major Genetic Syndromes

Table 8. Clinical Practice Guidelines for Diagnosis and Colon Surveillance of Familial Adenomatous Polyposis (FAP) continued...

Adenomas, serrated adenomas, and hyperplastic polyps can be seen in MAP patients. The CRCs tend to be right-sided and synchronous at presentation and seem to carry a better prognosis than sporadic CRC.[190] The Mallorca group and National Comprehensive Cancer Network (NCCN) have established clinical management guidelines based on available literature. These guidelines are generally consistent but have some differences related to age at initiation of surveillance. NCCN recommends beginning initiation at age 25 to 30 years repeated at 2 to 3 year intervals,[92] while the Mallorca group recommends surveillance beginning at age 18 to 20 years with upper-tract surveillance beginning at age 25 to 30 years.[191] The recommended surveillance interval can be based on the burden of involvement according to Spigelman criteria.[191] Total colectomy with ileorectal anastomosis may be appropriate for patients with MYH-associated polyposis, provided that they have no rectal cancer or severe rectal polyposis at presentation and that they undergo yearly endoscopic surveillance thereafter.[192]

Many extracolonic cancers have been reported in patients with MAP including gastric, small intestinal, endometrial, liver, ovarian, bladder, and thyroid and skin cancers including melanoma, squamous epithelial, and basal cell carcinomas.[193,194] Additionally, extracolonic manifestations have been reported in a few MAP patients including lipomas, congenital hypertrophy of the retinal pigment epithelium, osteomas, and desmoid tumors.[135,194,195,196] Female MAP patients have an increased risk of breast cancer.[197] These extracolonic manifestations seem to occur less frequently in MAP than in FAP, AFAP, or LS.[198,199]

Because MAP has an autosomal recessive inheritance pattern, siblings of an affected patient have a 25% chance of also carrying a biallelic MYH mutation and should be offered genetic testing. Similarly, testing can be offered to the partner of an affected patient so that the risk in their children can be assessed.

The clinical phenotype of monoallelic MYH mutations is less well characterized with respect to incidence and associated clinical phenotypes, and their role in pathogenesis of polyposis coli and colorectal carcinoma remains controversial. Approximately 1% to 2% of the general population carry a deleterious mutation in MYH.[5,135,137] In one cohort of 215 APC mutation-negative patients, eight monoallelic MYH mutation carriers had a later mean age at diagnosis (average 48 years compared with 43 years in MAP) and a high CRC incidence rate of 50%.[189] Monoallelic mutations were found in four patients with polyposis coli with 10 to 100 adenomas and in four patients with fewer than 10 adenomas; none of the monoallelic MYH mutation carriers had manifestation in the upper GI tract.[189] This is in contrast to past reports of extracolonic polyposis in 22% of monoallelic MYH mutation carriers.[200,201] The literature reports up to 4.4% frequency of monoallelic MYH carriers in CRC patients.[202] This incidence rate is above the carrier frequency in the general population (0%–2.1%),[203] suggesting a causative involvement in CRC. The risk of CRC in heterozygous carriers of single MYH mutations who are relatives of patients with MAP is comparable with that of first-degree relatives of patients with sporadic CRC.[187] Screening measures for monoallelic carriers could be based on this modest increase in risk (standardized incidence ratio [SIR] = 2.12; 95% confidence interval [CI], 1.30–3.28).[187] However, a 2007 meta-analysis of all previous case-control studies failed to support an increased risk of CRC in monoallelic MYH mutation carriers.[204]

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